During normal pregnancy, the decidua undergoes a tightly regulated process of apoptotic regression to accommodate the developing fetus. Recent studies from this laboratory indicate that activin A may act as a pro-apoptotic factor during this reorganization. In contrast, prolactin, which is produced by human and rodent decidua, acts as an anti-apoptotic factor in this tissue and is able to down regulate expression of activin A. Female mice lacking a functional prolactin or prolactin receptor gene undergo normal decidualization during early pregnancy, in the presence of exogenous progesterone, but are infertile due to fetal death and resorption from midpregnancy. We hypothesize that the anti-apoptotic effects of prolactin are carried out through inhibition of decidual activin A expression and that the absence of prolactin results in pregnancy failure due to premature expression of activin A in the decidua and a resulting disorganization in decidual apoptosis. Our specific aims are 1) to determine the mechanism by which prolactin inhibits activin A expression in the decidua, 2) determine whether the anti-apoptotic effects of prolactin are mediated through inhibition of activin A in the decidua, and 3) determine whether fetal death in the prolactin null mouse is due to premature expression of activin A and apoptosis in the decidua. We will address these aims by manipulating signal transduction molecules within cultured cells, treating cultured cells with prolactin, activin, and inhibitors, and examining decidual regression in prolactin-null animals.